A number of transition metal complexes have been found to be able to differentiate between double- vs. single-stranded DNA or B vs. Z helical forms of DNA through noncovalent recognition. This selectivity is primarily due to the binding of the transition metal complex in either the major or minor groove of duplex structures or in association with the nucleobases in unpaired strands. The electron-rich character of the nucleobases often makes them strong ligands for metals and efficient targets of oxidation. Guanine has been shown to have the highest affinity for coordination to transition metal ions and it is also the most easily oxidized, followed by adenine, cytosine and thymine (in order of ease of oxidation). Although base oxidation can be highly specific and directed to one site, strand scission has been shown to result from base oxidation only after treatment with subsequent heat and alkaline conditions.
Some complexes that exhibit direct strand cleavage in conjunction with sequence specificity are bleomycin.Fe(II) and the metallointercalator, [Rh(phen)2phi]3+. Although there is both a structural and a sequence requirement in each of these cases, the recognition criteria are not sufficiently unique to limit the number of target sites in DNA. Scission may be targeted specifically to one site by incorporating known DNA recognition elements into the ligand suprastructure of a well-characterized nucleolytic agent such as EDTA.Fe(II), which, when underivatized, promotes oxidative cleavage of DNA in a random fashion without nucleotide sequence selectivity. While this approach localizes cleavage to a site where the recognition element binds to DNA, the reaction is rarely constrained to a single nucleotide. Strand cleavage frequently extends over more than 5 bases. A longstanding goal of considerable interest has been to construct transition metal complexes that can mediate base oxidation and strand scission targeted to a single base with a significantly high level of recognition such that cleavage occurs at a limited number of sites along a target polynucleotide.
Most investigations focusing on oxidative strand scission of DNA by transition metals have typically relied on mononuclear complexes. Among these complexes, bis(1,10-phenanthroline)copper, [Cu(OP)2]2+, has been studied extensively due to its high nucleolytic efficiency. The cleavage pattern induced by [Cu(OP)2]2+ is predominantly sequence-neutral, although some variability in intensity due to local perturbations of DNA structure affects its efficiency. Also a slight, but distinct, preference for cleavage at 5′-AT-3′ and 5′-GT-3′ sites has been observed. Otherwise, [Cu(OP)2]2+ like EDTA.Fe(II) may be conjugated to binding elements such as proteins and complementary sequences of RNA or DNA that possess affinity for specific sites on DNA. Still, multiple sites adjacent to the locus of recognition are typically oxidized by these complexes even when tethered to a DNA recognition element.